The present invention relates to a novel method of preparing a novel chemical compound having antibacterial activity, which is useful in the therapy of bacterial infections in mammals. The compound is also itself useful as an intermediate in the synthesis of other antibacterial compounds. More specifically, the method of preparation of the present invention relates to derivatives of the well-known macrolide antibiotic, erythromycin A, the compound of the structure: ##STR1##
Even more specifically, the invention relates to a method of making 9-deoxo-9(Z)-hydroxy-iminoerythromycin A, the compound of the structure: ##STR2##
The (Z) geometric isomer of erythromyein A oxime has been unobtainable until now, with only the (E) geometric isomer having been previously achieved.
The C-9 carbonyl group of erythromycin A has been the focus of considerable chemical modification. For example, the ketone has been reduced to the 9-hydroxy derivative, and has been condensed with hydroxylamine and hydrazine to provide the corresponding oxime and hydrazone derivatives M. V. Sigal, Jr., P. F. Wiley, K. Gerzon, E. H. Flynn, U. C. Quark, and O. Weaver, J. Am. Chem. Soc., 1956, 78, 388. E. H. Massey, B. Kitchell, L. D. Martin, K. Gerzon, and H. W. Murphy, Tetrahedron Lett., 1970, 157. Of all the modifications at C-9, the oxime derivative is perhaps the most valuable substance both in terms of its antibacterial properties and as a substrate for further chemical modification. Alkylation of the oxime group has provided a variety of biologically interesting 9-alkoxyimino derivatives which includes the clinical candidate roxithromycin U.S. Pat. No. 4,349,545. The oxime group has also been reduced to the corresponding 9-imino and 9-amino derivatives, (4) G. H. Timms and E. Wildsmith, Tetrahedron Lett., 1971, 195 which have in turn served as platforms for further synthetic manipulation. A particularly promising derivative of the 9(S)-amino isomer is the clinical candidate dirithromycin. More recently, Beckmann rearrangement of erythromycin A oxime has led to a series of ring expanded 9a-aza-9a-homoerythromycin analogs possessing interesting antibacterial properties and improved pharmacokinetic properties S. Djokic, G. Kobrehel, G. Lazarevski, N. Lopotar, and Z. Tamburasev, J. Chem. Soc. Perkin Trans. I, 1986, 1881. A particularly valuable member of this series is the clinical candidate azithromycin.
The configuration of the oximino group in erythromycin A oxime has been assigned as (9E) based on comparison of its proton nuclear magnetic resonance (.sup.1 H NMR) spectrum with that of the major isomer of erythromycin B oxime R. S. Egan, L. A. Freiberg, and W. H. Washburn, J. Org. Chem., 1974, 39, 2492. The erythromycin B series differs from the erythromycin A series in that the 12-hydroxy group has been replaced by a hydrogen atom. In the erythromycin B series, a minor, unstable (9Z) oxime isomer was isolated and characterized by .sup.1 H NMR, .sup.13 C NMR and infrared spectroscopy. To date, this remains the first and only report of the isolation and characterization of an erythromycin Z-oxime ibid. Similar attempts to determine the configuration of the Z-form of erythromycin A oxime were thwarted by the unavailability of an isolable, minor isomer.
The present invention relates to a process for isomerizing the (9E)-isomer of erythromycin A oxime to the corresponding (9Z)-isomer and for isolating the heretofore unknown (9Z)-isomer as a stable, crystalline substance. Like the (9E)-isomer discussed above, the (9Z)-isomer also possesses antibacterial activity and serves as a substrate for further chemical modification leading to new products.